Method of prolonging release of drug from a precompressed solid carrier



United States Patent 07'' 3,087,860 METHOD OF PROLONGING RELEASE OF DRUGFROM A PRECOMPRESSED SOLID CARRIER Clarence J. Endicott, WinthropHarbor, Ill., assignor to Abbott Laboratories, North Chicago, 111., acorporation of Illinois No Drawing. Filed Dec. 19, 1958, Ser. No.781,433 11 Claims. (Cl. 167-82) This invention relates to a novel methodof prolonging the release of a drug from a solid carrier. Moreparticularly, the invention relates to the vapor treatment of a drugcomposition dispersed in a plastic carrier. This treatment fuses theindividual particles of plastic into a continuous network of plasticwhich impedes the release of the drug from the carrier when such acomposition is administered orally.

It has always been recognized in the medical art that the administrationof drugs by the oral route is to be preferred and in recent years moreand more emphasis has been placed on the oral administration of drugs.There are reasons why many drugs cannot be administered satisfactorilyin their simplest form. For example, the drug may be too readilyabsorbed with the consequent danger from toxic dosage. Secondly, it maybe too readily excreted and pass out of the body before the therapeuticeffect can be realized or the drug may be effective but prolongation ofits effect is desired to avoid multiple dosages.

Numerous attempts have been made to provide a dosage form which willsolve the foregoing problems but up to the present time none of thesehas proven entirely satisfactory. For example, enteric coatings havebeen applied for many years to a wide variety of drugs in an attempt toprotect the drug from gastric secretions, or to protect the stomach fromthe harsh effect of the drug. Enteric coatings have employed many kindsof materials and all are designed to be resistant to gastric secretions,but must be readily disintegrated in the intestinal tract in order forthe drug to become effective. In every instance the enteric coating isdesigned to prevent release of drug in the stomach and to be destroyedor broken up in the intestinal tract. Enteric cOatings as a class dependupon some type of chemical action or reaction for their disintegration.

Another class of protective coating for medieaments is the type known astime-disintegration coatings. In these coatings a class of materials isused which is dissolved or distinguished slowly as the tablet passesthrough the stomach and intestine, and an amount of coating is usedwhich is designed to allow release of the drug after a certain period oftime in the body. Due to the tremendous differences in the operation ofthe gastrointestinal mechanism in different persons thetime-disintegration coating does not work the same way in every personbut rather is designed to give results based on averages.

A variation of the time-disintegration dosage form just described is onein which particles of a medicament are coated with a varying number oflayers of a material which will be slowly washed away or destroyed bythe gastro-intestinal fluids. In such a dosage form a portion of thedrug has little or no coating for initial response, thin coatings areused for a quick follow-up response and thicker coatings are used for adelayed response.

Time-disintegration coatings as a class depend for their disintegrationupon the effects of agents found in the gastro-intest-inal fluids. Theenzymes, fat-solubilizers and emulsifiersin these fluids hasten thebreaking-up or wearing-away of the coatings.

It is a principal object of the present invention to pro- 3,087,860Patented Apr. 30, 1963 vide a method for the preparation of an orallyeffective dosage form in which the drug will be slowly released in thebody.

Another object of the invention is to provide a method for the vaportreatment of a drug composition dispersed in a plastic carrier whichwill coalesce the individual particles of plastic to impede the releaseof the drug when such a composition is orally administered.

A further object of the invention is to provide a method for thepreparation of an oral dosage form from which the drug will be slowlyreleased by a substantially physical process of dissolving drug out of asolid, inert body independently of the digestive process.

Other objects and many of the inherent advantages of the presentinvention will become more apparent throughout the followingspecification and appended claims.

In the accomplishment of the foregoing objects and in accordance withthe practice of this invention there is now provided a method for thevapor treatment of a combination of a drug and, if desired, awater-soluble excipient dispersed uniformly in a body of a non-toxicsynthetic plastic material. Such treatment produces a continuous networkwithin the carrier and makes it less susceptible to disintegration whensuch a drug combination is orally ingested. In general, the methodconsists of exposing a compressed mixture (conveniently in table form)of drug and plastic to the vapors of a volatile organic solvent for theplastic in a confined space for a period of time suflicient to result insoftening of the surface of said plastic.

Suitable solvents include methylene chloride, ethyl acetate, ethylenedichloride and toluene. In a preferred method of operation, acetone isemployed as the solvent. The compressed mixture of drug and plastic isexposed in a confined space at room temperature and atmospheric pressurefor a period of from 3 to 24 hours. Alternatively, the vapor treatmentmay be carried out at temperatures of about 100 F. at atmosphericpressure or at considerably higher temperatures and under vacuum.

Upon drying the treated tablet, the plastic particles adhere to oneanother more firmly forming a porous body having a network of continuousinterstices throughout the tablet. The plastic body resistsdisintegration during exposure to water. Before solvent vapor treatment,the

, plastic particles are so loosely held together that the tabletsdisintegrate within a very short time. Thus, it is believed that thetreatment results in a partial solubilization of the individualparticles of plastic by the solvent vapor and a fusion of one particleof plastic to another. When such a composition comes into contact withan aqueous liquid the drug is leached or diffused out of the plasticbody. The amount of drug released in the early stages of the leachingprocess is sufficient to provide the desired initial pharmacologicresponse and the amount of drug released thereafter will sustain thepharmacologic response over an extended period of time. Because thereleasing action is entirely physical, rather than chemical, the resultsare readily predictable.

The term drug is used herein in its broadest sense as indicating anysubstance or composition which will give a pharmacologic response. Whenit is said that the drug is water soluble it is meant to indicate thatthe drug must be soluble in aqueous liquids to at least a certain smallextent but drugs which are readily soluble in water will, of course,make up the preferred group. Methamphetamine salts, hexocycliummethylsulfate, paraamino benzoic acid, ephedrine, mannitol hexanitrate,amphetamine, erythromycin salts, penicillin salts, pentobarbital,phenobarbital, atropine, belladonna, theophylline, sex hormones,hydantoins, trimethadione, watersoluble vitamins such as B and C,benzazoline, toluidine blue and related drugs are representative of thebroad class of drugs which may be incorporated in compositions suitablefor treatment by this new method.

The plastics to which this invention pertains may be any syntheticresinous of polymeric material which is substantially inert togastro-intestinal liquids and which, of course, is essentially non-toxicand can be ingested without danger. The plastic mass or body may bereferred to as an orally ingestible plastic carrier, in which the drugis dispersed. It is desirable that the drug be uniformly dispersedthroughout the body or mass of the carrier in order that uniformity ofresults may be obtained. In a preferred form of the invention, it isdesirable to use a plastic carrier which is not only substantially waterinsoluble but which will be excreted substantially unchanged except forthe loss of the drug therefrom.

The polymers suitable for use in this invention must be resistant toflow, sintering or blocking at temperatures likely to be encountered instorage. While rubbery materials can be used, the manufacture of thefinished product is easier if the polymer is hard, i.e., in a glassy orcrystalline state at ambient temperature. Since the temperature at Whichpharmaceutical products may be stored may rise as high as 105 F., theglass point of a suitable polymer should preferably be not much lowerthan 105 F. The glass point is defined in Flory, Principles of PolymerChemistry, p. 56, Cornell University Press, 1953. Briefly, it is themidpoint of the narrow temperature region above which an amorphouspolymer exists in a viscous or rubbery condition and below which it ishard and relatively brittle.

There are numerous polymers and copolymers which can be usedsuccessfully in this invention as will be evident to those skilled inthe art. A few examples are polyethylene, polymethylmethacrylate,copolymers of methylmethacrylate and alkyl acrylates, polyvinylacetate,polyhexamethylene adipamide and the like.

The polymers can be prepared by bulk, solution, suspension, or emulsionpolymerization. If the last method is used, the polymer may becoagulated into solid particles which can be readily mixed with a drugor a drug may be admixed before coagulation as will be more fullydiscussed hereinafter.

In the polymerization procedure, it is desirable in some cases to use astep or steps in which impurities, if present, are removed. There shouldbe removed inhibitor, if used, residual monomer or monomers, and anyremaining polymerization initiator. Methods for accomplishing these endsare known in the art. They include distillation in its various aspectssuch as distillation with steam or under low pressure, washing andextraction.

The composition employed in the method of this invention may bedescribed as having discrete particles of a drug dispersed in a matrixof a plastic carrier. This composition is to be distinguished from aplastic tablet coating in which the coating completely surrounds thedrug and prevents access of liquids to the drug until the coating isdisrupted or destroyed. In the present instance, the plastic takes theform of a foraminous body with drug contained in the pockets or voids,but the drug is accessible to liquids and may be removed from theplastic body by a leaching or washing action without materiallyaffecting the phyiscal condition of the plastic body.

One may add sodium chloride or other water-soluble, component oringredient to increase the water permeability of the composition. Otherwater-soluble excipients or adjuvants which may be employed includedextrose, acacia, sucrose, polyethylene glycols, sorbitol, urea,polyvinylpyrrolidone, inositol, lactose, mannitol, methocel, calciumchloride, pectin and the like.

The composition employed in the method of this invention can be made ina number of ways which will be apparent to one skilled in the plasticsart. One suitable way of making the composition is to thoroughly blend aplastic in powder or granular form with the drug in crystalline orgranular form and then subject the mixture to heat and pressure so thatthe composition is converted into a solid body or mass having the drugdispersed therein. It is possible by the use of selected proportions ofparticles having different sizes to arrive at any desired rate ofdiffusion or leaching. This is an important and highly desirable featuresince it enables the compounder to adjust the rate of release of thedrug to a given set of conditions.

Another method is to disperse the drug in a liquid monomer, andpolymerize the mass, thereby achieving an excellent dispersion of thedrug in the plastic, which may then be comminuted to desired size. Thismethod may be varied by using mixtures of monomers, and by addingpolyfunctional monomers, which result in a cross-linked plastic,insolu-be in most solvents. By means of this latter technique, normallywater-soluble polymers and very hydrophilic polymers, such aspolyacrylic acid, may be employed in the invention.

Still other methods are contemplated. In addition to incorporation ofthe drug by milling or by mixing and extruding the drug-plasticcombination, a drug of limited water solubility may be finely ground andsuspended in a latex or aqueous dispersion of an appropriate plastic.The latex may then be coagulated by known procedures to give a finelydivided crumb in which the plastic and drug are intimately associated.Alternatively, a dispersion or solution of a drug in such a latex may bespray dried or drum dried and the solid product ground and screened togive a suitable product. In another method the plastic is dissolved in asolvent solution, the drug is dispersed or dissolved therein and thesuspension or solution cast as a film by known techniques. The film canbe ground and screened to proper size.

The amount of drug which is suspended or dispersed in the plastic massmay be varied at will from a small but significant amount capable ofgiving a pharmacologic response up to the saturation point beyond whichthe composition will no longer have its characteristic properties as aplastic mass. In one instance it was found that up to by weight of drugbased on the total weight of the composition can be employed. It will beapparent that the concentration of the drug, the particle size of thecomposition and the water permeability of the plastic mass provide agreat deal of control over the response of the drug and may beinterrelated in such a way as to give the compounder great leeway in thepreparation of tailored compositions.

The composition employed in the vapor treatment method of this inventionmay be prepared by grinding or otherwise comminuting the plastic masshaving the drug embedded therein to a desired particle size or range ofparticle sizes and mixing, combining or incorporating in apharmaceutical carrier. Particle size in an important aspect of theinvention since the rate of diffusion or leaching out of the drug from agiven plastic after vapor treatment will be slower from a small particlethan from a large particle. The particles may be recombined withtableting adjuvants in the form of conventional pharmaceutical tablets.

The following examples illustrate the invention but are not to beconstrued as a limitation thereof.

Example I Mg. Sodium p-aminobenzoate 8.26 Sodium chloride 24.80

Methylacrylate-methylmethacrylate copolymer 48.6

These tablets were exposed to acetone vapor in a closed container for 24hours at room temperature and after drying were tested for release ofthe drug by exposure to water with the following results:

6 v r ing the tablets with water. The results are tabulated below.

P t 1 Percent Percent 5 Time of exposure in minutes f fi hg ti s true ofexposure in minutes release of release of tr atment;

dtrngtbeforte grug after; 1'82, D1611 rea men a 15 29 12 22 ii 56 23 12047 73 36 240 69 2% 480 82 90 81 Before the acetone vapor treatment,these tablets release as much as 80% of the drug in one hour or less 1Sdapparent from i abgve l zl thefidmg Is 15 when exposed to water. Inaddition, the tablets disintei fi if g i 2 o g i er Z grate rapidlybefore treatment but remain intact after one t e P as w par 16 m w 6treatment even when all the drug is leached from the the drug 1suniformly dispersed form a continuous net- 1 p astic carrier. work ofVOld spaces throughout the tablets wh1ch resist Example 1V dismtegrationand permit the drug to be leached gradu- 20 ally from the plastic body.The plastic body is com- In another p r compressed tablets were ppletely intact as a single entity at the end of the leaching pared 111 amanner Wherem the amouhls of process each component are given below on aper tablet basis:

Example II Compressed tablets wherein all ingredients and amountsMethamphetamine hydrochloride 5 are on a per tablet basis were preparedin the normal Polyvmylpyrrohdone 26-41 manner;Methylacrylate-methylmethacrylate copolymer 77.37 M Talc t 5.36Hexocyclium methylsulfate 7 5 Magnesium stearateMithylaerylale'methylmethael'ylale P Y 30 These tablets were treatedwith acetone vapors in a vace uum chamber for 5 hours at a temperatureof 30 C. Magnesium stearate 3-3 and a pressure of 240 mm. of mercury.The tablets were The tablets were exposed to acetone vapor in a closedthen alr-dried overnight and finally oven-dried at 140 F. container for24 hours at room tempera/[ma The dried for 48 hours to remove all tracesof acetone. The treated tablets were then tested for the release of thedrug by exggg g ggig gggg g; g: lg f ig 2$ 2g:

osure to water th h f ll sults: P W t e o owmg re plastic carrierremained mtact after all the drug had been removed. Before the vaportreatment, the compressed I Percent Percent tablets disintegratedrapidly in water and released the drug Tune of exposure in minutesdgellgatsgfgie toef 40 within 30 to 60 minutes treatment treatment Instill other experiments, it was found that satisfactory results could beobtained so far as the gradual release of 23 i the drug and resistanceto disintegration of the plastic 32 carrier were concerned when thevapor treatment of com- 6 5 pressed tablets containing other drugs andplastics here- 22 87 inbefore enumerated was carried out with volatileorganic solvents such as methylene chloride, ethyl acetate and ethylenedichloride. Although acetone is the solvent of The abeve data clearlyIllustrates the effect of afietohe choice, it will be apparent to thoseskilled in the art that treatment 011 the release of the drug from thePlashe any solvent or mixture of solvents can be used in the presrier.With an untr at ta p i lly all Of the drug ent method provided it isvolatile at reasonable operating is released within 30 minutes. fteractone tre conditions and is a solvent for the particular plastic emagood initial release of the drug occurs which gives the l d as h carrierfor th d dosage level necessary for the desired therapeutic effect. I li After this initial dose, the liberation of the drug slows 1 Th h d fprolonging h release f a d f down to a more uniform pace over the nextseveral hours. a compressed mixture f drug and an inert water l Here gthe Plashe Phh afiihere t0 eaehpther more ble, non-toxic, non-brittle,synthetic polymer having a tenacwusly to prevent dlsmtegratwn andprovlde gradual glass point of at least 105 P. which comprises exposingrelease of the drug. said mixture to the vapors of a 'volatile organicsolvent for Exam le 1 0 said polymer in a confined space for a period oftime sufp ficient to result softening the surface of said polymer Thefollowing for-mualtion was compressed into tablets and thus fuse Thelhdlvldual P y Pameles throughout wherein all ingredients and amountsare given on a p the mixture into a foraminous structure to furtherembed tablet basis: the drug thereinlMg 2. The product produced by themethod of claim 1. Hexocyclium th l lfate 100 3. A method as claimed inclaim 1 wherein the polymer Carbowax 0 117 is a co-polymer ofmethylacrylate and methylmethacrylate. Methylacrylateqnethylmethacrylate1 117 4. A method as claimed in claim 3 wherein the solvent Talc 13,3employed is selected from the group consisting of acetone, Magnesiumstearate 6,6 methylene chloride, ethyl acetate, ethylene dichloride andtoluene. The tablets were thereafter subjected to acetone vapors 5. Themethod of prolonging the release of a drug in a closed container for 3hours at a temperature of 25 from an inert, water insoluble, non-toxic,non-brittle, syn- C. The tablets were then air dried and the release ofthe thetic polymer carrier having a glass point of at least 105' drugfrom the tablets was determined in vitro by contact- F. which comprisesexposing a compressed tablet of said drug and said carrier to acetonevapors in a confined space for a sufficient period of time to soften andcoalesce the individual particles in said carrier into a foraminousstructure throughout the tablet to further embed the drug therein.

6. The product produced by the method of claim 5.

7. A method as claimed in claim 5 wherein the drug is selected from thegroup consisting of hexocyclium methylsulfate, methamphetaminehydrochloride, nicotinic acid, phenobarbital sodium and sodiumparaminobenzoate.

8. A method as claimed in claim 5 wherein the polymer carrier isselected from the group consisting of polyethylene, polyvinylacetate,polymethylmethacrylate and methylacrylate-methylmethacrylateco-polymers.

9. The method of prolonging the release of methamphetamine hydrochloridefrom a non-toxic, inert, water insoluble, non-brittle, syntheticmethylacrylate-methylmethacrylate co-polymer which comprises exposing acompressed tablet of said hydrochloride and said c0- polymer to acetonevapors in a vacuum chamber for about 5 hours at a temperature of about30 C. and a pressure of about 240 millimeters of mercury to fuse theindividual particles of co-polymer throughout the tablet into aforaminous structure to further embed the drug therein.

10. A method of prolonging the release of hexocyclium methylsulfate froma non-toxic, inert, water insoluble, non-brittle, syntheticmethylacrylatemethylmethacrylate co-polymer which comprises exposing acompressed tablet of said sulfate and said co-polymer to acetone vaporsin a closed container for about 24 hours at room temperature to fuse theindividual particles of co-polymer throughout the tablet into aforaminous structure to further embed the drug therein.

'11. The method of treating the human body which comprises administeringto a human host the product produced by the method of claim 5, saidproduct being 3 adapted to release an efiective amount of drug graduallyover a period of time during which the said product is present in thebody.

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1. THE METHOD OF PROLONGING THE RELEASE OF A DRUG FROM A COMPRESSEDMIXTURE OF DRUG AND AN INERT, WATER INSOLUBLE, NON-TOXIC, NON-BRITTLE,SYNTHETIC POLYMER HAVING A GLASS POINT OF AT LEAST 105*F. WHICHCOMPRISES EXPOSING SAID MIXTURE TO THE VAPORS OF A VOLARILE ORGANICSOLVENT FOR SAID POLYMER IN A CONFINED SPACE FOR A PERIOD OF TIMESUFFICIENT TO RESULT IN SOFTENING THE SURFACE OF SAID POLYMER AND THUSFUSE THE INDIVIDUAL POLYMER PARTICLES THROUGHOUT THE MIXTURE INTO AFORAMINOUS STRUCTURE OF FURTHER EMBED THE DRUG THEREIN.